Abstract:

The present invention relates to a pharmacologic dosage unit which
includes a multi-functional particulate system and a pharmacologically
active agent. The multi-functional particulate system includes solid
biologically-safe particles incorporated into a matrix and having a
characteristic that each individual particle retains its original size.
The invention also relates to methods of preparing, enhancing flow
properties and compacting properties of a pharmacologic composition,
increasing capacity for inclusion of ingredients, and increasing
dispersion of actives. Finally, the invention includes a method for
delivering an active agent to a patient.

Claims:

2. A dosage unit according to claim 1 selected from the group consisting
of tablets, sachets, lozenges, hard capsules, softgels, troches, dragees,
suppositories, and the like

3. A dosage unit according to claim 2, which is a compressed tablet.

4. A dosage unit according to claim 1 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a weight ratio of 1:99 to 99:1, and (iv)
wherein the mean weight diameter of resulting particulates have a size of
from 25 to 500 microns.

16. A dosage unit according to claim 15 wherein said pharmacologically
active agent is acetaminophen.

17. A dosage unit according to claim 15 wherein said pharmacologically
active agent is Coenzyme Q10.

18. A dosage unit according to claim 15 wherein said pharmacologically
active agent is encapsulated.

19. A method of preparing a pharmacologic dosage unit comprising:admixing
a multi-functional particulate system and a pharmacologically active
agent in amounts requisite to provide a pharmacologic composition capable
of use as an ingredient for inclusion in a pharmacologic dosage unit.

20. A method according to claim 19, wherein said dosage unit is selected
from the group consisting of tablets, sachets, lozenges, hard capsules,
softgels, troches, dragees, suppositories, and the like.

21. A method according to claim 20 wherein said pharmacologic composition
has enhanced flowability.

22. A method according to claim 20 wherein said dosage unit is a
compressed tablet.

23. A method according to claim 22 wherein said pharmacologic composition
has enhanced comparability.

24. A method according to claim 19 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a weight ratio of 1:99 to 99:1, and (iv)
wherein the mean weight diameter of resulting particulates have a size of
from 25 to 500 microns.

36. The method according to claim 35 wherein said pharmacologically active
agent is acetaminophen.

37. The method according to claim 35 wherein said pharmacologically active
agent is Coenzyme Q10.

38. The method according to claim 35 wherein said pharmacologically active
agent is encapsulated.

39. A method for making a pharmacologic dosage unit comprising:(i)
admixing a multi-functional particulate system and a pharmacologically
active agent in amounts requisite to provide a pharmacologic composition
which is sufficiently flowable and compactable to form a compressed
tablet; and(ii) compacting the mixture resulting from step (i)
sufficiently to form a compressed tablet.

40. A method according to claim 39, wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a weight ratio of 1:99 to 99:1, and (iv)
wherein the mean weight diameter of resulting particulates have a size of
from 25 to 500 microns.

41. A method according to claim 40 wherein said matrix is
biologically-safe and is selected from the group consisting of
polysaccharides, modified polysaccharides, sugars, gum, thickeners,
stabilizers, syrups, flours, starches, dextrose, maltodextrins,
cellulose, and combinations thereof.

42. A method according to claim 39 wherein the multi-functional
particulate system displays a loose bulk density of 0.1 to 1.1 kg/L.

43. A method according to claim 39 wherein the mean weight diameter of the
multi-functional particulate system is from 50 to 400 microns.

44. A dosage unit according to claim 40 wherein said weight ratio between
particles and matrix ranges from 20:80 to 80:20.

45. A dosage unit according to claim 40 wherein said weight ratio between
particles and matrix ranges from 40:60 to 60:40.

46. A method according to claim 40 wherein said particles have a discrete
particle size of 2 to 275 microns.

47. A method according to claim 40 wherein said particles are
nutritionally active.

50. The method according to claim 49 wherein said pharmacologically active
agent is acetaminophen.

51. The method according to claim 49 wherein said pharmacologically active
agent is Coenzyme Q10.

52. The method according to claim 49 wherein said pharmacologically active
agent is encapsulated,

53. A process for enhancing flow properties of a pharmacologic composition
used as an ingredient for a pharmacologic dosage unit comprising:adding a
multi-functional particulate system to at least one pharmacologically
active agent in an amount sufficient to improve flowability of said
active agent in its use as an ingredient for making a pharmacologic
dosage unit.

54. A process according to claim 53 wherein said dosage unit is selected
from the group consisting of tablets, sachets, lozenges, hard capsules,
softgels, troches, dragees, suppositories, and the like.

55. A process according to claim 54 wherein said dosage unit is a
compressed tablet.

56. A process according to claim 53 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present, in a weight ratio of 1:99 to 99:1, and
(iv) wherein the mean weight diameter of resulting particulates have a
size of from 25 to 500 microns.

62. A process according to claim 61 wherein said pharmacologically active
agent is acetaminophen.

63. A process according to claim 61 wherein said pharmacologically active
agent is Coenzyme Q10.

64. A process according to claim 61 wherein said pharmacologically active
agent is encapsulated.

65. A process for enhancing compacting properties of a pharmacologic
composition used as an ingredient for a pharmacologic dosage unit
comprising:adding a multi-functional particulate system to at least one
pharmacologically active agent in an amount sufficient to provide or
improve compactability of said active agent whereby it can be used as an
ingredient for making a pharmacologic dosage unit.

66. A process according to claim 65 wherein said dosage unit is selected
from the group consisting of tablets, sachets, lozenges, hard capsules,
softgels, troches, dragees, suppositories, and the like.

67. A process according to claim 66 wherein said dosage unit is a
compressed tablet.

68. A process according to claim 65 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a weight ratio of 1:99 to 99:1, and (iv)
wherein the mean weight diameter of resulting particulates have a size of
from 25 to 500 microns.

74. A process according to claim 73 wherein said pharmacologically active
agent is acetaminophen.

75. A process according to claim 73 wherein said pharmacologically active
agent is Coenzyme Q10.

76. A process according to claim 73 wherein said pharmacologically active
agent is encapsulated.

77. A method for delivering a pharmacologically active agent to a patient,
comprising:administering to a patient, in need of treatment with at least
one pharmacologically-active agent, a pharmacologic dosage unit,
comprising:(i) at least one pharmacologically active agent suitable for
said treatment of said patient, and(ii) a multi-functional particulate
system.

78. A method according to claim 77 wherein said dosage unit is selected
from the group consisting of tablets, sachets, lozenges, hard capsules,
softgels, troches, dragees, suppositories, and the like.

79. A method according to claim 78 wherein said dosage unit is a
compressed tablet.

80. A method according to claim 77 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a weight ratio of 1:99 to 99:1, and (iv)
wherein the mean weight diameter of resulting particulates have a size of
from 25 to 500 microns.

86. A method according to claim 85 wherein said pharmacologically active
agent is acetaminophen.

87. A method according to claim 85 wherein said pharmacologically active
agent is Coenzyme Q10.

88. A method according to claim 85 wherein said pharmacologically active
agent is encapsulated.

89. A method for increasing capacity for inclusion of at least one
ingredient in a pharmacologic dosage unit comprising:adding a
multi-functional particulate system to a pharmacologic composition used
in a pharmacologic dosage unit in an amount sufficient to increase the
amount of at least one other ingredient in said composition.

90. A method according to claim 89 wherein said dosage unit is selected
from the group consisting of tablets, sachets, lozenges, hard capsules,
softgels, troches, dragees, suppositories, and the like.

91. A method according to claim 90 wherein said dosage unit is a
compressed tablet.

92. A method according to claim 89 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a w;eight ratio of 1:99 to 99:1, and
(iv) wherein the mean weight diameter of resulting particulates have a
size of from 25 to 500 microns.

98. A method according to claim 97 wherein said pharmacologically active
agent is acetaminophen.

99. A method according to claim 97 wherein said pharmacologically active
agent is Coenzyme Q10.

100. A method according to claim 97 wherein said pharmacologically active
agent, is encapsulated.

101. A method according to claim 89 wherein said pharmacologic composition
comprises an excipient selected from the group consisting of silicified
microcrystalline cellulose, vinyl-pyrollidone vinyl-acetate copolymer, or
combinations thereof.

102. A method for increasing dispersion of pharmacologically active agents
within a pharmacologic dosage unit comprising:adding a multi-functional
particulate system to at least one pharmacologically active agent in an
amount sufficient to provide or improve dispersion of said
pharmacologically active agent whereby its inclusion as an ingredient in
a pharmacologic dosage unit is facilitated.

103. A method according to claim 102 wherein said dosage unit is selected
from the group consisting of tablets, sachets, lozenges, hard capsules,
softgels, troches, dragees, suppositories, and the like.

104. A method according to claim 103 wherein said dosage unit is a
compressed tablet.

105. A method according to claim 102 wherein said multi-functional
particulate system comprises: (i) solid biologically-safe particles, (ii)
incorporated into a matrix, (iii) said incorporation having a
characteristic that each individual particle retains its original size
and said matrix being present in a weight ratio of 1:99 to 99:1, and (iv)
wherein the mean weight diameter of resulting particulates have a size of
from 25 to 500 microns,

[0002]Compressed tablets are well known in the art of delivering
pharmacologically active ingredients. They provide a convenient and
efficient vehicle for delivering uniform doses of pharmacologically
active ingredients. However, there are several divergent technical
requirements which must be met in order to implement manufacture of
pharmacologically active dosage units in the form of compressed tablets.

[0003]For example, in order to ensure accurate and uniform delivery of the
required amount of active ingredient, a substantially homogeneous blend
of different tablet ingredients must be prepared and maintained
throughout the tableting process. This requirement can be quite difficult
to achieve, especially when the active ingredient(s) resists blending.
Thus, pharmacologically active ingredients which are, inter alia, fine,
cohesive, etc., such as acetaminophen, can present very difficult
tableting problems resulting in non-uniform doses and/or inferior
tablets.

[0004]Furthermore and closely related to maintaining uniformity of
mixture, a tableting mixture must have a good flow characteristic. This
means that the mixture is able to flow through the machinery which
delivers it to the tableting press in such a way that that the mixture
remains uniform and flowable without substantial discontinuity.

[0005]Another characteristic required of the tableting mixture is that h
demonstrates good compactability at reasonable compression forces. To a
certain degree maintaining this characteristic can he inimical to
maintaining a thorough and homogenous mixture with good flowability.
Basically, highly flowable, thoroughly-mixed ingredients many times
resist compaction under reasonable compression forces.

[0006]As a result of requirements such as those set forth above and
others, tablet manufacturers are required to call upon many and sometimes
expensive ingredients to meet the particular deficiencies of specific
tableting mixtures. Furthermore, expensive tableting equipment and/or
modifications thereof can be required for processing different tableting
mixtures.

[0007]Finally, since delivery of certain active ingredients require
different types of release profiles, even further modifications and/or
ingredients must be made to mixtures and equipment and processing
parameters in order to achieve the desired release in the host patient.
Consequently those skilled in the art continuously search for new and
better methods and ingredients to enhance tablet mixing and tablet
formation to engineer the correct compressed tablet for each application.

[0008]Therefore, it is the purpose in the present invention to provide a
new and unexpectedly effective composition and method for processing and
making dosage units for delivering a pharmacologically active ingredient.

SUMMARY OF THE INVENTION

[0009]The present invention is a pharmacologic dosage unit which includes
a pharmacologically active agent and a multi-functional particulate
system. The present invention also includes methods of preparing and
making a pharmacologic dosage unit. Other aspects of the invention
involve processes for enhancing flow properties and compacting properties
of a pharmacological composition used as an ingredient for a
pharmacologic dosage unit. Additionally, the invention involves a method
for delivering a pharmacologically active agent to a patient and a method
for increasing capacity for inclusion of at least one ingredient in a
pharmacologic dosage unit.

[0010]Dosage units of the present invention include, but are not limited
to, tablets, sachets, lozenges, hard capsules, softgels, troches,
dragees, suppositories, and the like. A preferred dosage unit is a
compressed tablet.

[0011]The dosage units contain a pharmacologically active agent and a
multi-functional particulate system. The multi-functional particulate
system includes, (i) solid biologically-safe particles, (ii) incorporated
into a matrix, (iii) and having a characteristic that each individual
particle retains its original size and the matrix, being present in a
weight ratio of from 1:99 to 99:1, and (iv) such that the mean weight
diameter of resulting particulates have a size of from 25 to 500 microns.

[0012]The matrix is a biologically-safe material that can be selected from
the group consisting of polysaccharides, modified polysaccharides,
sugars, gums, thickeners, stabilizers, syrups, sugar alcohols, flours,
starches, dextrose, maltodextrins, cellulose, and combinations thereof.
Preferably, the matrix material is sugar or mixtures of sugars.

[0013]In a preferred embodiment, the multi-functional particulate system
displays a loose bulk density of from about 0.1 to about 1.1 kg/L. In
another preferred embodiment, the mean weight diameter of the
multi-functional particulate system is from 50 to 400 microns.
Preferably, the weight ratio between the particles and the matrix ranges
from 80:20 to 20:80, and more preferably 40:60 to 60:40. The particulate
has discrete particles with a size in the range of from 2 to 275 microns.
The particles can be nutritionally active.

[0014]The particles which are used in the multi-functional particulate
system are biologically-safe and can be inorganic substances such as
Na2CO3, NaHCO3, K2CO3, KHCO3, CaCO3,
Ca(HCO3)2, CaSO4, Ca(NO3)2, CaSO3,
Ca(HSO3)2, MgCO3, Mg(HCO3)2, and Ca(HPO4),
and Ca3(PO4)2, or organic substances such as celluloses,
polysaccharides, and polymerics. The particles can also be
biologically-safe acids such as citric acid, maleic acid, tartaric acid,
maleic acid, lactic acid, acetic acid, and combination thereof, and
derivatives and salts thereof. In a particularly preferred embodiment,
the particle is CaCO3.

[0016]In a particularly preferred embodiment, the pharmacologically active
agent can be acetaminophen. Another pharmacologically active agent can be
the cofactor Coenzyme Q10(CoQ10).

[0017]In another embodiment, the invention relates to a method of
preparing a pharmacologic dosage unit. The method involves admixing a
multi-functional particulate system and a pharmacologically active agent
in amounts requisite to provide a pharmacologic composition capable of
use as an ingredient for inclusion in a pharmacologic dosage unit. The
pharmacologic composition has enhanced flowability and enhanced
comparability. These features are particularly valuable when the dosage
unit being prepared is a compressed tablet.

[0018]In yet another embodiment, the invention relates to a method for
making a pharmacologic dosage unit comprising (i) admixing a
multi-functional particulate system and a pharmacologically active agent
in amounts requisite to provide a pharmacologic composition which is
sufficiently flowable and compactable to form a compressed tablet, and
(ii) compacting the mixture resulting from step (i) sufficiently to form
a compressed tablet.

[0019]In another embodiment, the invention relates to a process for
enhancing the flow properties of a pharmacologic composition used as an
ingredient for a pharmacologic dosage unit. The process involves adding a
multi-functional particulate system to at least one pharmaceutically
active agent in an amount sufficient to improve flowability of the active
agent in its use as an ingredient for making a pharmacologic dosage unit.

[0020]In yet another embodiment, the invention relates to a process for
enhancing compacting properties of a pharmacologic composition used as an
ingredient for a pharmacologic dosage unit. The process involves adding a
multi-functional particulate system to at least one pharmaceutically
active agent in an amount sufficient to provide or improve compactability
of the active agent whereby it can be used as an ingredient for making a
pharmacologic dosage unit.

[0021]In another embodiment the invention relates to a method for
delivering a pharmacologically active agent to a patient. The method
involves administering to a patient, in need of treatment with at least
one pharmacologically-active agent, a pharmacologic dosage unit,
containing (i) at least one pharmacologically active agent suitable for
treatment of the patient and (ii) a multi-functional particulate system.

[0022]In yet another embodiment, the invention relates to a method for
increasing capacity for inclusion of at least one ingredient in a
pharmacologic dosage unit. The method involves adding a multi-functional
particulate system to a pharmacologic composition used in a pharmacologic
dosage unit in an amount sufficient to increase the amount of at least
one other ingredient in the composition. The pharmacologic composition
may contain silicified microcrystalline cellulose, vinyl-pyrollidone
vinyl-acetate copolymer, or combinations thereof

[0023]In another embodiment, the invention related to a method for
increasing dispersion of pharmacologically active agents within a
pharmacologic dosage unit. The method involves adding a multi-functional
particulate system to at least one pharmacologically active agent in an
amount sufficient to provide or improve dispersion of said
pharmacologically active agent whereby its inclusion as an ingredient in
a pharmacologic dosage unit is facilitated.

[0024]For a better understanding of the present invention, together with
other and further advantages, reference is made to the following detailed
description, and its scope will he pointed out in the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0025]The present invention provides a pharmacologic dosage unit which
includes a pharmacologically active agent and a multi-functional
particulate system.

[0026]The pharmacologic dosage unit can be in forms that are delivered
orally or rectally and may include, but are not limited to, tablets,
caplets, minitablets, sachets, lozenges, hard capsules, softgels,
troches, dragees, sublingual tablets, buccal tablets, suppositories, and
the like. The preferred dosage units are compressed tablets and capsules.

Compressed Tablets

[0027]Compressed tablets can be made according to various methods well
known in the art. For example, see Rudnic, E., and Schwartz, J. B. Oral
Solid Dosage Forms, Chapter 92, Tablets, pp. 1615-1641, in Remington's,
19th Ed.

[0028]Compressed tablets can be administered to a patient by numerous
means. For example, the compressed tablets may be swallowed or chewed.
The application may be sublingual, buccal, enteric, immediate release,
controlled release, rapid dissolve, modified release delayed release, or
pulsatile release.

[0029]The compressed tablets of the present invention contain
pharmacologically active agents and a multi-functional particulate
system. The tablets may also contain other ingredients such as additives
that serve a variety of different functions.

[0031]The pharmacologically active agent can also be encapsulated. For
example, the active agent may be encapsulated in a polymer and/or other
coating materials such as lipids. Polymer and lipids for use as
protective coatings of an active agent are known to those skilled in the
art. Lipids usually are fat and fat-like substances which are derived
either synthetically or from plants or animals.

Multi-Functional Particulate System

[0032]The multi-functional particulate system contains solid
biologically-safe particles incorporated into a matrix. The particles are
incorporated in a manner in which each individual particle retains its
original size.

[0033]The mean weight diameter as measured using sieve analysis of the
resulting particulate system ranges from 25 to 500 microns. Preferably
the mean weight diameter ranges from 2 to 275, more preferably from 5 to
250 microns, and most preferably from 7 to 200 microns.

[0034]The matrix can be selected from abroad range of materials as long as
they are biologically-safe. Preferably, the matrix is selected from the
following: polysaccharides, modified polysaccharides, sugars, gums,
thickeners, stabilizers, syrups, sugar alcohols, flours, starches,
dextrose, maltodextrins, and celluloses. Most preferably, the matrix is
composed of a sugar or mixtures of sugars. The particle size of the
matrix materials can vary between 1 and 400 microns, preferably between 5
and 200 microns, more preferably between 25 and 100 microns.

[0035]Preferably, the multi-functional particulate system displays a loose
bulk density of 0.1 to 1.1, more preferably 0.3 to 0.6 kg/L. Loose bulk
density is measured by measuring the volume of a known mass powder
sample, that has passed through a screen into a gradulated cylinder. The
procedure is described in USP<616<Bulk Density and Tapped Density.

[0036]The biologically-safe particles are in the matrix in a weight ratio
of 1:99 to 99:1. Preferably, the weight ratio is 20:80 to 80:20, and most
preferably from 40:60 to 60:40.

[0037]The particles can be of very different nature. In particular,
nutritionally active particles that improve the oral properties of the
dosage unit, or the bioavailability of the particle or the dispensability
of the particle in a dosage unit have proven to be very useful. Preferred
particles have low water solubility.

[0039]The discrete particle size of the biologically-safe particle in the
total particulate system suitably ranges from of 2 to 275 microns.
Preferably the particle size is 5 to 250, and most preferably 7 to 200
microns.

[0041]Disintegrating agents enhance the rate of which the tabletted
multi-functional particulate system disintegrates. Examples of
disintegrating agents include, but are not limited to, crosscarmellose
sodium, sodium starch glycolate, cross-linked polyvinylpyrollidone, soy
polysaccharides, pregelatinized starches, calcium silicate, sugar
combinations, or combinations thereof or agents which increase salivation
in the oral cavity such as organic acids, including, but not limited to,
citric, maleic, or tartaric acid and their encapsulated, or otherwise
modified forms.

[0042]Other ingredients which can be included in the dosage unit of the
present invention include binders. Binders generally contribute to the
ease of formation and general quality of the dosage units. Non-limiting
examples of binders include starches, pregelatinized starches, gelatin,
polyvinylpyrrolidone, methyl cellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose,
ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and
polyvinyalcohols.

Enhanced Flowability

[0043]Flowability of an ingredient such as a pharmacological composition
for making a dosage unit can be defined as the property of the
composition, e.g., powder or granulate, which enables it to flow through
processing machinery and ultimately into a dosage-forming station. Poorly
flowing compositions such as powders present many difficulties in the
pharmaceutical industry in processing and dosage-forming, especially in
the making of compressed tablets and filled capsules. It is, indeed,
desirable to provide a free flowing composition, e.g., a powder, so that
certain advantages can be realized such as those set forth below:

[0044](a) the composition easily flows into and through a machinery which
passes it along for dosage-forming;

[0045](b) as a consequence of uniform tablet weight and uniform doses of
active ingredient, other parameters of finished tablets such as hardness,
friability, disintegration characteristics, dissolution and plasma levels
in the body are reproducible;

[0046](c) high uniformity of the compressing composition or powder and,
therefore, less wear on the machine;

[0047](d) ease of ejection of air during compression because of good
permeability and, therefore, fewer defective tablets due to capping or
splitting; and

[0048](e) high production rate allowed by the easily-flowing rate of a
free flowing composition.

[0049]Many efforts have been made to overcome problems created by
poor-flow properties by studying different formulations and applying
different manufacturing techniques. At the same time many attempts have
been made to establish experimental procedures having practical
industrial significance which can measure or assess the intrinsic
flowability of the powder to be encapsulated or compressed. A number of
authors identified the powder flowability with the interparticulate
friction, of which an "angle of repose" is a manifestation (E. Nelson--J.
Am. Pharm. Assoc. Sci. Ed. 44, No. 7, 435-437 (1955)) and at least four
practical methods of measuring the angle of repose have been developed
which are described and compared by David Train in J. Pharm. Pharmacol.
10, 127T to 135T (1958).

[0050]Basically, according to the "angle of repose" method the powdered
material is allowed to fall freely through an orifice onto a flat surface
to form a conical pile of deposited material and the angle between the
surface of the cone and the horizontal plane is known as the angle of
repose. A high angle would indicate a poorly flowing material whereas a
low angle would indicate good flow.

[0051]Timed delivery through an orifice is another method often used for
evaluating the flowability of materials. A timer, e.g., a stop watch, is
used to either time certain weights of powder flowing through the orifice
or to close the orifice after a given time so that the powder flowing
through in a designated time period can he weighed.

[0052]Ausburger and Shangraw (J. Pharm. Sci., 55, No. 4, 418-423 (1966)),
attempted to evaluate and compare the free flowing properties of powders
using the weight and weight variation of the finished tablets as the
measured parameter. It was believed, in fact, that the weight variation
of both capsules and tablets is directly dependent upon the
reproducibility of powder flow into a fixed volume receptable (which may
be a tablet die cavity or a capsule shell) and that good precision, which
reflects in a high tablet weight and lower coefficient of variation, can
only be obtained when the powder to be filled has a good flowability.
This method can be conveniently used in routine quality control tests.

[0053]A further method for determining the free flow properties of a
powder has been described in DEGUSSA Schriftenreihe, Anwendungstechnik
Pigmente Nr. 31 (Wolfgang Hanau (Main)) pages 6 to 8 and is based on how
the powder runs through sand timer-like funnels with varying orifices.
The equipment there described consists of a series of five glass funnels
with orifice diameters of 2.5, 5, 8, 12, and 18 mm, and the powder
flowability in ranked as outstanding, very good, good, acceptable or poor
depending on the diameter of the orifice which the powder can still pass
through.

[0054]And, in U.S. Pat. No. 4,274,286, an apparatus for measuring the
flowability of powder is disclosed which utilizes a container having a
bottom wail with an opening therein. The bottom wall may be changed to
provide openings of different sizes. The test consists of allowing the
powder to flow through successively smaller holes. The smallest hole size
through which the powder will freely flow is a measure of its
flowability.

[0055]In any event, by use of one or more of the methods set forth above,
pharmacologic compositions prepared in accordance with the present
invention have been found to exhibit greater flowability than, at least,
the active component by itself and without the inclusion of the
multi-functional particulate. In fact, active ingredients such as CoQ10
exhibit virtually no flowability in the absence of the multi-functional
particulate of a present invention. Moreover, the use of the
multi-functional particulate and pharmacologic compositions resulting
therefrom also enables (or improves) ingredients other than actives also
be useable in dosage unit production machines in the pharmaceutical
industry. These enhanced flowability characteristics are especially
useful in making compressed tablets and in filling capsules.

Enhancing Compactability and Dispersion of Actives

[0056]The present invention also includes the aspect of improving the
comparability of a pharmacological composition which includes a
pharmacologically active agent. By use of a multi-functional particulate
of the present invention, a composition can be prepared, e.g., powder
and/or particulate, which improves its compactability when compared to
compactability of the active ingredient itself. In recent years
pharmacologically active ingredients are routinely used in lower amounts
per unit dosage than ever before and require the highest degree of
accuracy possible. In order to implement these requirements, the
additional ingredients must be capable of homogenously diluting the
active ingredient and provide a sufficient reduction in the amount of
elasticity and cohesivity to predictably separate and isolate
mechanically grains of active ingredient.

[0057]Likewise, cohesive pharmacologically active ingredients cause
problems during processing of dosage units because cohesive active
ingredients clump together and remain substantially indispersable.
Indispersable actives leads to the inability to create a uniform dosage
unit. By use of the multifunctional particulate of the present invention,
islands or "clumps" of active are virtually eliminated.

[0058]Consequently, the present invention provides a pharmacologic
composition which is useful in preparing direct compression tablets, and
low compression pre-formed inserts for use in capsule type unit dosage
forms. Pre-forms can be prepared by "tamping") rather than direct high
pressure compression.

Enhancing Carrying Capacity

[0059]The multi-functional particulate delivery system of the present
invention also increases the capacity for inclusion of at least one
ingredient in a pharmacologic dosage unit. For example, acetaminophen can
be incorporated into the multi-functional particulate at higher
percentage levels and successfully tabletted than compared to a
formulation without the multi-function particulate.

[0060]Additionally, excipients can be added to the multi-functional
particulate to further increase the carrying capacity of at least one
ingredient. Examples of useful excipients include silicified
microcrystalline cellulose, vinyl-pyrollidone vinyl-acetate copolymer, or
combinations thereof. ProSolv/S630 is seven-to-one blend of silicified
microcrystalline cellulose and vinyl-pyrollidone vinyl-acetate copolymer.

[0061]In the examples section, the carrying capacity of the
multi-functional particulate delivery system is measured. The carrying
capacity refers to the amount of a specific ingredient which can be
incorporated into a particular dosage unit.

[0062]Methods of measuring carrying capacity are well known to
practitioners in the art. For example, the carrying capacity of a tablet,
is measured by taking into account the hardness range of the tablet, the
amount of lbs of compression required to form the tablet, and the amount
of lbs required to eject the tablet from the tableting machinery.

Method of Making

[0063]The invention also relates to a method of preparing a pharmacologic
dosage unit. The dosage unit is made by admixing a multi-functional
particulate system and a pharmacologically active agent in amounts
requisite to provide a pharmacologic composition capable of use as an
ingredient for inclusion in a pharmacologic dosage unit.

[0064]In another embodiment, the invention relates to a method of making a
pharmacologic dosage unit by admixing a multi-functional particulate
system and a pharmacologically active agent in amounts requisite to
provide a pharmacologic composition which is sufficiently flowable and
compactable to form a compressed tablet, and compacting the resultant
mixture sufficiently to form a compressed tablet.

[0065]Multi-functional particulate systems can be made by methods known in
the art. A description of making a multi-functional particulate can be
found in U.S. Pat. No. 6,673,383which is incorporated herein by
reference.

[0066]Other processes typically used for powder granulations can also be
used to produce the multi-functional particulate system, such as low and
high shear mixer granulators.

[0067]For example, the multi-functional particulate system can be made
using a fluid-bed drier top spray. The solid biologically-safe particles
and a portion of the matrix components are combined. The remaining matrix
components, preferably maltodextrin and dextrose, are mixed together with
warm water at 25° C. to form a spray solution.

[0068]The outlet temperature and air volume are set to fluidize the
particle/matrix mixture. Then, the spray solution is sprayed onto the
particle/matrix mixture. The optimal spray rate and atomization air
pressure can be determined without undue experimentation. For instance, a
spray rate of 60 grams per minute with an atomization air pressure of 2.8
bar can be used.

[0069]After the mixture is completely sprayed, the multi-functional
particulate is dried. The determination of optimal outlet air temperature
and length of drying are within the purview of a person skilled in the
art. For example, the particulate can be dried at an outlet air
temperature of 40° C. for 5 minutes.

[0070]The multi-functional particulate can then be measured for loss on
drying. A Metier LP-16 Moisture Balance can be used for this
determination.

[0071]The last step involves passing the particulate through a sifter to
remove oversized materials. For instance, a US#20 mesh and Sweco Sifter
can be used.

[0072]Admixing a multi-functional particulate system to a
pharmacologically active agent can be accomplished by various methods
known in the art. Tumble mixers are often employed.

[0073]For example, a multi-functional particulate system and a
pharmacologically active agent can be added to a V-blender, then mixed
for an appropriate period of time at a given speed. The length of time
and speed of rotation is subject to such factors as the active agent
employed, the amount of multi-functional particulate, and the
multi-functional particulate employed. Such variations are within the
capabilities of those skilled in the art without the need for undue
experimentation.

[0074]The invention also involves a method of making a pharmacologic
dosage unit. The method involves admixing a multi-functional particulate
system with a pharmacologically active agent in an amount sufficient to
provide a flowable and compactable compressed tablet ingredient or
mixture, and compacting the mixture to form a compressed tablet which can
be recovered from compaction and stored and made available to a patient
as a dosage unit.

[0075]Methods of compacting mixtures to form a compressed tablet are well
known. A person skilled in the art would be able to determine, without
the need for undue experimentation, the appropriate amounts of pressure
to apply to the mixture, the optimal amounts of multi-functional
particulate to include in the mixture, and the additives to include in
order to create a tablet that could be recovered from compaction and
stored.

[0076]The features and advantages of the present invention are more fully
shown by the following examples, which are provided for purposes of
illustration, and are not to be construed as limiting the invention in
any way.

[0079]The 6×powder sugar, calcium carbonate, 1.085 kg of dextrose,
and macrocrystalline cellulose were placed into a bowl. The maltodextrin
and the remaining 0.03 kg of dextrose were mixed in warm water at
25° C. (1.0% solids in solution) as the spray solution.

[0080]An outlet temperature range of about 38° C. was used and an
air volume sufficient (damper 1/2 open) to fluidize the product was set.
The spray solution was sprayed onto the product in the bowl at a spray
rate of 60 grams per minute with an atomization air pressure of 2.8bar.

[0081]Upon completion of the spray solution, the multi-functional
particulate system was dried at an outlet air temperature of 40°
C. for 5 minutes. The multi-functional particulate system was sized on a
US#20 mesh using a Sweco Sifter to remove any oversized material.

[0082]The multi-functional particulate system described above was used in
the formulations below.

Example 2

Compaction of the Multi-Functional Particulate System

[0083]Tablets of various weights (between 1160 and 2600 mg) containing
only the multi-functional particulate system were made. The compression
profile for the 2000 mg tablets was measured.

[0086]All three formulations tabletted without any problem. The
multi-functional particulate system by itself can be tabletted at
reasonable compression forces to create tablets within a good hardness
range.

[0087]The second table shows that compressibility and comparability were
acceptable when direct tableting the multi-functional particulate system,
since both thickness (i.e., tablet volume) and hardness were sensitive to
compression force.

[0089]The multi-functional particulate system with 10% acetaminophen
showed excellent compactability, A plateau starts at 5000 lb compression,
with breakdown taking place between 7000 and 8000 lb. The plateau is the
point at which the hardness does not increase with added compression. The
plateau begins at high compression indicating that the multi-functional
particulate system can easily carry 10% acetaminophen.

[0090]Acceptable compactability is found up to about 5000 lb compression,
Above that compression, breakdown sets in. The multi-functional
particulate system shows acceptable carrying capacity for 20%
acetaminophen.

[0094]This experiment was performed to determine the carrying capacity of
multi-functional particulate systems (see formulation 2d.). In addition
to 44% Acetaminophen and the same amount of multi-functional particulate
system, there was about 11% ProSolv/S630 in the compression mix.

[0095]The Prosolv/S630 (7/1), 44% Acetaminophen, and Multi-functional
Particulate System mixture shows a substantial improvement over
formulation 2d. ProSolv/S630 works synergistically with the
multi-functional particulate system to increase carrying capacity of
Acetaminophen.

[0098]Additional formulations made at higher Acetaminophen (>60%) and
increased ProSolv levels produced tablets with hardness below 2.0 kP,
indicating that the carrying capacity of multi-functional particulate
systems/ProSolv/S630 system is about 50% Acetaminophen, which is
approximately 20% greater than the multi-functional particulate system
alone.

[0099]Ubidecarenone (ubiquinone; CoQ 10) does not flow due to its cohesive
character. It also has content-uniformity issues in solid dosage forms.
Therefore, it is extremely difficult to tablet by itself.

[0100]The multi-functional particulate system was used to disperse the
fine particles of CoQ10and enhance flow. Colloidal silica (CabOSil) and
high-density silicified microcrystalline cellulose (ProSolv HD90) were
used as blending agents.

[0102]CabOSil with ubidecarenone is co-sieved through a 30-mesh. The
ProSolv HD90 and multi-functional particulate system are added. The
powder mix is blended at maximum speed for ten minutes. The powder mix is
then sieved through a 40-mesh. Polyplasdone Crospovidone is added, and
the mixture is blended at maximum speed for two minutes Finally,
Mg-stearate is added, and the mixture is blended at maximum speed for two
minutes.

[0103]The powder mixture showed remarkable improvement in flow. The bulk
density of the final blend was 0.45 g/mL. The incorporation of a
multi-functional particulate system with a substantially unflowable
particle like CoQ10 allows it to flow.

Example 6

Incorporation of Encapsulated Pharmacological Agents

[0104]The present experiment was performed to determine applicability of
encapsulated vitamin C (Vitashure® 160 sold by Bale-hem Corporation)
for making 500 mg active Vitamin C tablets, using multi-functional
particulate systems as the main filler, and to measure the compression
profile.

[0106]Excellent tablets were made. The high tensile strength Indicates
good compatibility between components, and also that sorbitol is a
complementary excipient in this system.

[0107]Thus, while there have been described what are presently believed to
be the preferred embodiments of the present invention, other and further
embodiments and modifications can be made without departing from the
spirit of this invention, and it is intended to include all such
embodiments and modifications which come within the scope of the
invention as set forth in the appended claims.